Hi everybody,
53BP1 is known to block single strand resection which is an essential mechanism for the Homologous Repair DNA pathway, and by consequence, promotes the NHEJ pathway. In BRCA1 mutated cells, Inhibition of 53BP1 favor a reactivation of HR pathway. The consequence is an apparition of PARP inhibitors resistance. My question is, if the inhibition of 53BP1 promotes the HR pathway, why is there a resistance with PARPi (which promote ssDNA breaks and after dsDNA breaks) but seems to improve the IR hypersensitivity of cells (which triggers ssDNA and dsDNA breaks as well) ? I'm really confused about that and I don't if I am enough clear in my question. So don't hesitate to ask me to be more clear :)
Thank you for your help
The mechanism of PARPi therapy for BRCA1 mutant cancer is Synthetic Lethality, require both HR deficient resulted from BRCA1 mutant and decreased single-strand breaks repairing mediated by PARP inhabitation, so both BRCA1 mutant and PARPi are supposed to induce accumulated DNA damages. If HR pathway are restored or promoted by 53BPI inhabitation in BRCA1 mutant cells, dsDNA breaks will decrease, and relieve DNA damages, cells will become less sensitive to PARPi.
This paper might answer your question better.
DOI 10.1016/j.cell.2010.03.012
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